The Nelson-Aalen method was used in the total cohort (n = 119 151; n = 118 607 with data on all covariates) and adjusted for age; sex; smoking; diastolic blood pressure; use of antihypertensive medication and nitroglycerin at admission; and use at discharge of antihypertensive, statin, antiplatelet, anticoagulant, and other lipid-lowering medication. P values refer to comparisons between quartiles.

Figure 2. Hazard Ratio and Systolic Blood Pressure at Admission for 1-99 Percentiles of Participants in the Total Cohort

Data were stratified on age in 10 categories and adjusted for age; sex; smoking; diastolic blood pressure; use of antihypertensive medication and nitroglycerin at admission; use at discharge of antihypertensive, statin, antiplatelet, anticoagulant, and other lipid-lowering medication. The graph is based on fractional polynomials with powers 2 and 1. Dashed lines indicated 95% confidence intervals.

Table 1. Patient Characteristics at Admission to the Hospital for Chest Pain

Context High resting blood pressure (BP) is among the best studied and established risk factors for cardiovascular disease. However, little is known about the relationship between BP under acute stress, such as in acute chest pain, and subsequent mortality.

Design, Setting, and Participants Data from the RIKS-HIA (Registry of Information and Knowledge About Swedish Heart Intensive Care Admissions) was used to analyze the mortality in relation to supine admission systolic BP in 119 151 participants who were treated at the ICU for the symptom of chest pain from 1997 through 2007. Results from this prospective cohort study were presented according to systolic BP quartiles: Q1, less than 128 mm Hg; Q2, from 128 to 144 mm Hg; Q3, from 145 to 162 mm Hg; and Q4, at or above 163 mm Hg.

Main Outcome Measure Total mortality.

Results Mean (SD) follow-up time was 2.47 (1.5) years (range, 1-10 years). One-year mortality rate by Cox proportional hazard model (adjusted for age, sex, smoking, diastolic BP, use of antihypertensive medication at admission and discharge, and use of lipid-lowering and antiplatelet medication at discharge) showed that participants in Q4 had the best prognosis (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.72-0.80, Q4 compared with Q2; corresponding risks for Q1 were HR, 1.46; 95% CI, 1.39-1.52, and for Q3, HR, 0.83; 95% CI, 0.79-0.87). Patients in Q4 had a 21.7% lower absolute risk compared with Q2, patients in Q3 had a 15.2% lower risk than in Q2, and patients in Q1 had a 40.3% higher risk for mortality than in Q2. The worse prognosis in Q2 compared with Q4 was independent of body mass index and previous diagnoses and similar when analysis was restricted to patients with a final diagnosis of angina or myocardial infarction (HR, 0.75; 95% CI, 0.71-0.80, Q4 compared with Q2).

Conclusion Among patients admitted to the ICU for chest pain, there is an inverse association between admission supine systolic BP and 1-year mortality rate.

High blood pressure (BP) when measured after a standardized resting period is among the best studied and established risk factors for cardiovascular disease.1- 3 A pronounced elevation of systolic BP during stress, such as during a treadmill test, is also associated with an unfavorable long-term prognosis.4 Hypertensive patients with poor BP control often exhibit a tendency to show increases in BP during different kinds of stress, which is associated with increased sensitivity to BP-elevating hormones due to thickened vascular smooth muscle in arterioles.5 On the other hand, the increase in BP that some patients exhibit when recorded at the office or clinic, compared with ambulatory BP levels outside the office, is only weakly associated with an unfavorable long-term prognosis.6 In a pronounced stressful situation, when being admitted to hospital for acute congestive heart failure (CHF), low BP actually confers a poor prognosis in both the short-term and long-term.7 However, this finding most likely reflects that BP levels are low in severe cases of CHF because of the failing left ventricle. Patients admitted for CHF with relatively high BP have lower rates of left ventricular dysfunction compared with patients displaying low admission BP.7 It was shown in the Framingham cohort that low diastolic BP is associated with poor prognosis,8 and this finding was confirmed in a study of patients with stable coronary disease.9

Although postdischarge mortality and morbidity rates in coronary artery disease have declined considerably in the last decades because of improvements in treatment, there still remains a high risk for death after discharge from the intensive care unit (ICU), and information that identifies high-risk patients would likely be helpful in reducing postdischarge mortality. Accordingly, we studied death rate in relation to systolic BP measured at admission to the ICU for chest pain during 1997 through 2007 by analyzing data from 119 151 unselected patients in the RIKS-HIA (Registry of Information and Knowledge About Swedish Heart Intensive Care Admissions), which includes all Swedish hospitals. Because systolic and diastolic BP levels divert at higher ages, as systolic BP increases and diastolic BP decreases,10 we were interested in studying risks related to systolic rather than diastolic BP levels. The large sample size made it possible to also study subgroups, such as patients with diabetes mellitus and those who were discharged with a diagnosis of myocardial infarction (MI) or ischemic heart disease.

METHODS

The RIKS-HIA includes all patients admitted to the medical ICUs of all Swedish hospitals. Data for approximately 100 different variables were reported in case record forms, as has been described elsewhere.11- 13 The registry includes information on age, sex, smoking, previous MI, atrial fibrillation, diabetes, hypertension, cholesterol levels, angina pectoris, previous coronary revascularization, previous medications, symptoms, electrocardiogram at entry, biochemical markers, pharmacological treatment, revascularization procedures, major complications, concomitant diagnoses and outcomes during the hospital stay, and medications at discharge. (The full protocol is available at http://www.riks-hia.se) To ensure the validity of the information, a specially trained monitor visited participating hospitals and compared information in the patient records, including electrocardiograms, with information entered into the RIKS-HIA database for 30 to 40 randomly chosen patients for each hospital.13 Data quality was monitored in 5446 random records from all participating hospitals comprising 299 530 measurements, and there was a 94% overall agreement between registry information and patient records. Only participants with a pulse pressure greater than 9 mm Hg were included in the current analyses.

Mortality data were obtained by merging the RIKS-HIA database with the National Death Registry, including information on the vital status of all Swedish citizens through December 31, 2007. Previous history of stroke, renal failure, chronic pulmonary disease, dementia, cancer, heart failure, and peripheral vascular disease was obtained by merging with the National Patient Registry, which includes diagnoses for all patients hospitalized in Sweden from 1987 forward. Participating hospitals enrolled patients consecutively, and systolic BP at admission was defined as the measurement first obtained at presentation to the medical ICU. This BP was recorded with the patient resting in the supine position.

Ethics

The RIKS-HIA registry, and merging its data with other registries, was approved by the National Board of Health and Welfare and the Swedish Data Inspection Board. The ethics committee of Uppsala University Hospital approved the study. All patients for whom data were entered into RIKS-HIA gave their informed consent for participation in the registry (patients could request to be excluded) and the long-term follow-up.

Statistics

Statistical analyses were performed (M.F.) with Stata version 10.1 (StataCorp, College Station, Texas). In the main statistical analyses, a Cox regression (proportional hazard model) was used. A model containing systolic BP, both continuous and in quartiles with quartile 2 as reference, was mainly used, adjusted for age; sex; smoking; diastolic BP; use of antihypertensive medication and nitroglycerin at admission; and use at discharge of antihypertensive, statin, antiplatelet, anticoagulant, and other lipid-lowering medication. Body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, was considered but usually not included in the results because BMI data were missing for approximately 52% of patients. (Patient BMI was not part of regular RIKS-HIA data until 2004.) The assumption of proportionality was not fulfilled regarding age; therefore, analyses were stratified on age divided into deciles. In most of the analyses, systolic BP was categorized in quartiles. Other ways of categorizing were considered but did not change the result regarding systolic BP in any substantial way. A χ2 test was used for the analysis of a trend in the quartiles of systolic BP. Systolic BP was also used as a continuous variable in a Cox regression. Fractional polynomials were used with powers 2 and 1.14 The power of the study when comparing 1-year mortality in quartile 1 with quartile 2, quartile 3 with quartile 2, and quartile 4 with quartile 2 was more than 99% in all comparisons. Statistical significance was set as P < .05 and all tests were 2-sided.

RESULTS

We identified all participants in the RIKS-HIA admitted with chest pain to medical ICUs in Sweden from 1997 to the end of December 2006 who had a potential follow-up time of at least 1 year (ie, for whom data on mortality were collected until the end of December 2007). We excluded 0.1% participants because their pulse pressure was less than 10 mm Hg. The final study cohort comprised 119 151 participants. Table 1 lists patient characteristics in the cohort and in the quartiles of systolic BP at admission. Systolic BP in the first quartile (Q1) was less than 128 mm Hg; the second quartile (Q2) was from 128 to 144 mm Hg; the third quartile (Q3), 145 to 162 mm Hg; and the fourth quartile (Q4), at or above 163 mm Hg. Mean (SD) follow-up time for all patients was 2.47 (1.5) years (range, 1-10 years).

One-year mortality rate by Cox proportional hazard model (adjusted for age; sex; smoking; diastolic BP; use of antihypertensive medication and nitroglycerin at admission; and use at discharge of antihypertensive, statin, antiplatelet, anticoagulant, and other lipid-lowering medication) showed that participants in Q1 of systolic BP had highest risk for death; conversely, patients in Q4 had the best prognosis (hazard ratio [HR], 0.76, 95% confidence interval [CI], 0.72-0.80, for Q4 compared with Q2) (Table 2 and Figure 1). Corresponding adjusted absolute risks were a 21.7% lower absolute risk for death within 1 year for patients in Q4 compared with Q2. The mortality risk was 15.2% lower for patients in Q3 compared with Q2 while the risk for patients in Q1 was 40.3% higher for mortality compared with that in Q2.

The adjusted continuous relationship between systolic BP and 1-year mortality HR is presented in Figure 2. The risk for death was progressively lower at a higher systolic BP up to a level of approximately 200 mm Hg. When the data were split into 30 equally sized systolic BP data sets, participants in the upper 3.3% had an adjusted HR of 0.70 with a 95% CI of 0.62-0.78 compared with patients within the systolic BP reference interval of 151 to 154 mm Hg.

The finding of lower mortality in participants with high admission BP was unaffected when data were also adjusted for presence of known diabetes, dementia, malignancy, and previous MI and stroke, and it was also consistent when the follow-up time was extended to 3 years (3-year mortality HR for Q4 compared with Q2, 0.73; 95% CI, 0.69-0.77). The finding of lower mortality in participants with high admission BP was present when data for participants who died in the hospital (n = 1419) were removed (Q4 vs Q2 1-year mortality HR, 0.78; 95% CI, 0.74-0.82, in the remaining data set). Restriction of the data set by adjusting for BMI (n = 57 308 with complete data) did not affect the principal finding of a more favorable prognosis in Q4 compared with Q2 (1-year mortality HR, 0.74; 95% CI, 0.69-0.79).

A similar relationship between a high BP and good prognosis in the subsequent year was found also in the subset of the 21 488 patients with diabetes, although as suspected, a higher mortality rate was recorded than in the total cohort (Q4 vs Q2 1-year mortality HR for patients with known diagnosis of diabetes at admission, 0.83; 95% CI, 0.75-0.91). The finding of lower risks in Q3 and Q4 compared with Q2 was consistent also when data for participants with diabetes and participants with CHF were excluded (eAppendix). The 43 987 patients who were discharged with a diagnosis of MI also displayed the same principal relationship between a high admission BP and prognosis (1-year mortality HR for Q4 compared with Q2, 0.74; 95% CI, 0.68-0.79). The better prognosis in Q4 compared with Q2 was evident when death due to cardiovascular disease was set as the outcome instead of total mortality (1-year cardiovascular mortality HR for Q4 compared with Q2, 0.66; 95% CI, 0.58-0.74).

Patients with a final diagnosis of ischemic heart disease (ie, MI or angina), also had a more favorable prognosis if the admission systolic BP was high. Hazard ratios and absolute risks adjusted for medication and other potential confounders for participants with ischemic heart disease are in Table 3. The corresponding absolute 1-year mortality was 20.3% lower in Q4 than in Q2 among these patients. Addition of BMI to the model resulted in a corresponding 1-year mortality HR of 0.72 when comparing Q4 with Q2 (95% CI, 0.67-0.78, adjusted for potential confounders with the addition of BMI; n = 35 717 with complete data on all variables).

Patients in Q2 of systolic BP who did not show proof of any cardiovascular disease during the stay at the hospital also had a worse prognosis than those of Q4 (diagnosis of chest pain and no other diagnosis at discharge: 1-year HR for Q4 compared with Q2, 0.81; 95% CI, 0.68-0.97) (eAppendix). The reason for chest pain in these patients was not known because follow-up after discharge was not part of this registry and not structured for scientific purposes. The participants who were not found to have cardiac disease during the stay at the hospital had clinically very similar BP levels as the patients who were discharged with a diagnosis of MI (mean [SD] BP for those with no cardiovascular disease: 147.5 [25] mm Hg systolic and 81.8 [14] mm Hg diastolic; for those with MI, 145.6 [29] mm Hg systolic, 82.3 [17] mm Hg diastolic; P < .001 for both systolic and diastolic BP levels). However, heart rate at admission was about 10% higher in patients who did develop MI (mean [SD] rate, no cardiovascular disease, 72.4 [16]/min; MI, 79.5 [23]/min; P < .001).

COMMENT

High supine systolic BP measured in patients with acute chest pain was associated with a favorable 1-year prognosis. This was not caused by low systolic BP being a marker of subclinical CHF because high BP was related to good prognosis also when data were excluded for participants who already had or did develop a diagnosis of CHF. Low systolic BP is often present in CHF and has been shown to be a marker of poor prognosis in a substudy of 5791 participants.7 In our study, participants showed progressively better prognosis in Q2 through Q4, which also makes it unlikely that low BP due to a failing left ventricle was the underlying mechanism for the relatively poor prognosis in patients with low BP.

Furthermore, the poorer outcome of patients in Q1 could not be explained by use of antihypertensive agents among these patients because the statistical analyses adjusted for such use. However, it is possible that factors not present in the RIKS-HIA database, such as malnutrition or anemia, might explain part of the relatively poor prognosis associated with low admission systolic BP in our study. Although the lack of such data affects the interpretation of our results, it does not diminish the usefulness of the main findings in the acute clinic setting of a medical ICU, and the finding of an association of good prognosis with high systolic BP was unaffected when calculations were adjusted for BMI.

A potential weakness in our study was that all variables including BP were entered consecutively by whoever performed the measurement. Despite this shortcoming, the results presented here show that the prognostic value of the recorded systolic admission BP is still valid when adjusted for a large set of potentially confounding variables including diastolic BP. The fact that the measurement of BP and other variables was performed in an ordinary clinic setting speaks in favor of the usefulness, for general prognostic purposes, in the corresponding clinic setting, as compared with results from randomized controlled trials, which ordinarily use specific inclusion and exclusion criteria in screening participants.

Early risk stratification of patients with acute coronary syndromes is important in clinical decisions regarding treatment alternatives. Our study results support the feasibility of incorporating systolic admission BP in risk scoring models and are consistent with a US prospective investigation of 6-month postdischarge all-cause mortality risks in patients with acute chest pain, in which information about vital status was available for 87.5% of the enrolled 17 142 participants.15 In that study, a systolic BP less than 200 mm Hg at admission was associated with a poor prognosis.15 However, our study was considerably larger and covered a longer follow-up time, which allowed for adjustments for diastolic BP and substudies of patients with a final diagnosis of ischemic heart disease and participants without a diagnosis of CHF. Our study had complete follow-up data on mortality because each Swedish citizen is given a unique identification number, ensuring that no participants are lost to follow-up with respect to mortality. It can also be noted that when data were adjusted for medication use, antihypertensive medication at admission was related to a relatively poor prognosis while some medication at discharge (excluding diuretic therapy but including statins and antiplatelet therapy) was related to a good prognosis (Table 2). This is most likely due to the fact that medication use at admission is related to presence of disease while medication use at discharge affects the prognosis during the study follow-up time. When restricting the analysis to participants who were diagnosed with angina or MI, the association of a good prognosis and medication use at discharge (excluding diuretics) was more evident than in the total cohort.

Our data should not be interpreted as a suggestion not to normalize an elevated BP in patients with acute chest pain. Indeed, Amar et al16 have shown that uncontrolled hypertension is common after an acute coronary event and that presence of isolated systolic hypertension under such circumstances is associated with a poor prognosis. Blood pressure levels presented here were not “uncontrolled” but were measured before treatment began in the medical ICU to reduce pain and high BP. The data presented here should consequently only be used to add prognostic information in that particular context.

CONCLUSION

There is an inverse association between admission supine systolic BP and 1-year mortality rate in patients admitted to the medical ICU for chest pain. This finding also applies to those patients who are diagnosed with ischemic heart disease and those who eventually develop MI.